Novel Therapies for Cholestasis

The Liver Meeting 2017: American Association for the Study of Liver Diseases (AASLD)

William F. Balistreri, MD


December 13, 2017

A Novel Strategy for Pruritus 

Partial external biliary diversion, a procedure that interrupts the enterohepatic circulation of bile acids, is a surgical option for the relief of pruritus in children with cholestasis. It has been postulated that pharmacologic inhibition of the enterohepatic circulation may relieve symptoms of cholestasis and offer an alternative to surgical disruption.

Two clinical trials of maralixibat (LUM001; SHP625), a minimally absorbed inhibitor of the ileal/apical sodium-dependent bile acid transporter (IBAT/ASBT), were presented.

Shneider and colleagues[3] tested the hypothesis that maralixibat would reduce pruritus in patients with Alagille syndrome. Patients were randomly assigned to receive either once-daily placebo or maralixibat (70, 140, or 280 μg/kg/day) for 13 weeks.

Pruritus was assessed using a novel pediatric version of the Itch Report Outcome (ItchRO™) and a clinician-reported scratch scale, both of which grade the severity of reported itching on scale of 0-4 (none to severe). Liver chemistries, serum bile acid, and 7-alpha-hydroxy-4-cholesten-3-one (C4, a marker of bile acid biosynthesis) were measured serially.

The primary outcome of mean change in reported itching from baseline to week 13 varied from -0.58 in the placebo group to -1.47 in the group receiving 70 μg/kg, -1.49 in the 140-μg/kg group, and -0.62 in the 280-μg/kg group. The percentage of patients with a decrease in the degree of itching from baseline to week 13 was higher among those who received maralixibat than those who received placebo for both scales (ItchRO: 65% vs 25%; clinician-reported scratch scale: 76% vs 25%, respectively). Improvement of three or more grades occurred in six of 11 maralixibat recipients and in none of the 9 placebo recipients. Serum bile acid levels changed minimally, presumably owing to a compensatory increase in C4, supporting the biological activity of maralixibat.

Adverse events were similar between maralixibat and placebo recipients. Although the prespecified primary analyses of pruritus were not all statistically significant, the data suggest that maralixibat is safe and may reduce pruritus in patients with cholestasis.

In an analogous study, Thompson and colleagues[4] reported 48-week data from a phase 2 multicenter study of maralixibat in children with progressive familial intrahepatic cholestasis (PFIC). Maralixibat doses were escalated from 14 to 280 µg/kg/day over 13 weeks (depending on tolerability) and maintained for approximately 60 weeks.

Overall trends in key efficacy measures indicated clinically significant improvement from baseline to week 48 in response to maralixibat: serum bile acid levels were reduced, pruritus improved, and alanine aminotransferase, aspartate aminotransferase, and/or bilirubin levels normalized in participants with baseline elevations. This was most evident in the subset of participants with PFIC2; there was no improvement in participants with PFIC1.

Treatment-emergent adverse events judged to be related to maralixibat were common and led to discontinuation in one participant.

In a pilot trial, Al-Dury and colleagues[5] assessed the tolerability and effect of the selective IBAT inhibitor A4250 on pruritus in patients with primary biliary cholangitis.

All patients exposed to A4250 reported an improvement in pruritus. Serum autotaxin activity, a biomarker associated with pruritus, decreased during A4250 treatment. There was a high incidence of bile acid malabsorption-related diarrhea and abdominal pain in the study population, which the investigators reasoned was related to a starting dose of A4250 that may have been too high, and should be acknowledged in further studies of this compound.

These studies, while somewhat disappointing, support further clinical studies of inhibition of ileal bile acid reuptake, via ASBT inhibitors, as pharmacotherapy for patients with cholestatic pruritus. Determination of optimal dosing and further assessments of safety and efficacy in patients with cholestasis are warranted.

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